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HMG-CoA reductase inhibition aborts functional differentiation and triggers apoptosis in cultured primary human monocytes: a potential mechanism of statin-mediated vasculoprotection.

Vamvakopoulos JE, Green C - BMC Cardiovasc Disord (2003)

Bottom Line: Immunomodulatory actions, independent of their lipid-lowering effect, have also been ascribed to these compounds.Concurrent treatment with mevalonolactone prevented the induction of apoptosis and suppressed both IL-1beta and IL-1Ra release in response to LPS, suggesting a rate-limiting role for HMG-CoA reductase in monocyte differentiation.Our findings indicate that statins arrest the functional differentiation of monocytes into macrophages and steer these cells into apoptosis, suggesting a novel mechanism for the vasculoprotective properties of HMG-CoA reductase inhibitors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, University of Cambridge, Cambridge, UK. joannis@scientist.com

ABSTRACT

Background: Statins effectively lower blood cholesterol and the risk of cardiovascular death. Immunomodulatory actions, independent of their lipid-lowering effect, have also been ascribed to these compounds. Since macrophages participate in several vascular pathologies, we examined the effect of statin treatment on the survival and differentiation of primary human monocytes.

Methods: Peripheral blood mononuclear cells (PBMCs) from healthy individuals were cultured in the presence or absence of mevastatin. Apoptosis was monitored by annexin V / PI staining and flow cytometry. In parallel experiments, cultures were stimulated with LPS in the presence or absence of mevastatin and the release of IL-1beta and IL-1Ra was measured by ELISA.

Results: Among PBMCs, mevastatin-treated monocytes were particularly susceptible to apoptosis, which occurred at doses >1 microM and was already maximal at 5 microM. However, even at the highest mevastatin dose used (10 microM), apoptosis occurred only after 24 h of culture, possibly reflecting a requirement for cell commitment to differentiation. After 72 h of treatment the vast majority (>50%) of monocytes were undergoing apoptosis. Stimulation with LPS revealed that mevastatin-treated monocytes retained the high IL-1beta output characteristic of undifferentiated cells; conversely, IL-1Ra release was inhibited. Concurrent treatment with mevalonolactone prevented the induction of apoptosis and suppressed both IL-1beta and IL-1Ra release in response to LPS, suggesting a rate-limiting role for HMG-CoA reductase in monocyte differentiation.

Conclusions: Our findings indicate that statins arrest the functional differentiation of monocytes into macrophages and steer these cells into apoptosis, suggesting a novel mechanism for the vasculoprotective properties of HMG-CoA reductase inhibitors.

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Statin-mediated monocyte apoptosis in the context of atherosclerosis. During formation of the atherosclerotic plaque monocytes are recruited and retained in the vascular wall, where they differentiate into macrophages. Macrophages incorporate lipids giving rise to foam cells, which exhibit a dysregulated phenotype possibly due to oxidative stress. Mature macrophages and foam cells are thought to promote plaque rupture by eroding the fibromuscular cap. This is likely achieved through release of matrix-degrading proteases and also via FasL-mediated cytotoxic effects on adjacent vascular smooth muscle cells. Statins modulate both primary vascular release of MCP-1 and monocyte chemotaxis. In situ monocyte apoptosis might also contribute to their downstream effects on plaque stability.
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Figure 4: Statin-mediated monocyte apoptosis in the context of atherosclerosis. During formation of the atherosclerotic plaque monocytes are recruited and retained in the vascular wall, where they differentiate into macrophages. Macrophages incorporate lipids giving rise to foam cells, which exhibit a dysregulated phenotype possibly due to oxidative stress. Mature macrophages and foam cells are thought to promote plaque rupture by eroding the fibromuscular cap. This is likely achieved through release of matrix-degrading proteases and also via FasL-mediated cytotoxic effects on adjacent vascular smooth muscle cells. Statins modulate both primary vascular release of MCP-1 and monocyte chemotaxis. In situ monocyte apoptosis might also contribute to their downstream effects on plaque stability.

Mentions: Monocyte turnover in solid tissue is determined by the balance between recruitment and clearance. Overproduction of monocyte chemoattractant protein (MCP-1) by native vascular cells and macrophages is a major mechanism promoting macrophage accumulation in atherosclerotic [32,33] and neointimal [34,35] lesions. Statin treatment was recently shown to down-regulate MCP-1 production in vitro and in vivo [36]; and to suppress the release of various other atherothrombotic mediators by plaque macrophages [15,36-40]. However, in most cases, the potential contribution of cell death to these findings was not concurrently investigated. Here we show that HMG-CoA reductase inhibition suppressed the release of IL-1Ra from LPS-stimulated monocytes; but that this suppression was largely accounted for by apoptotic cell death. Unlike IL-1β, the release of which occurs via stimulation of the P2X7 receptor at the level of the cell surface [41] and is thus refractory to apoptosis, secretion of IL-1Ra follows the classical pathway, which is effectively shut down during apoptosis [42]. While suppression of endothelial MCP-1 synthesis might genuinely contribute to the benefits of statin therapy, we suggest that induction of monocyte apoptosis may underlie many downstream statin actions, including the reduction in plaque macrophage counts and inhibition of in situ MMP and TF production [37-40] (figure 4). It is noteworthy that, since osteoclasts are also developmentally derived from peripheral blood monocytes, this hypothesis fits well with the recently proposed role of statins as modulators of bone formation [43].


HMG-CoA reductase inhibition aborts functional differentiation and triggers apoptosis in cultured primary human monocytes: a potential mechanism of statin-mediated vasculoprotection.

Vamvakopoulos JE, Green C - BMC Cardiovasc Disord (2003)

Statin-mediated monocyte apoptosis in the context of atherosclerosis. During formation of the atherosclerotic plaque monocytes are recruited and retained in the vascular wall, where they differentiate into macrophages. Macrophages incorporate lipids giving rise to foam cells, which exhibit a dysregulated phenotype possibly due to oxidative stress. Mature macrophages and foam cells are thought to promote plaque rupture by eroding the fibromuscular cap. This is likely achieved through release of matrix-degrading proteases and also via FasL-mediated cytotoxic effects on adjacent vascular smooth muscle cells. Statins modulate both primary vascular release of MCP-1 and monocyte chemotaxis. In situ monocyte apoptosis might also contribute to their downstream effects on plaque stability.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC183828&req=5

Figure 4: Statin-mediated monocyte apoptosis in the context of atherosclerosis. During formation of the atherosclerotic plaque monocytes are recruited and retained in the vascular wall, where they differentiate into macrophages. Macrophages incorporate lipids giving rise to foam cells, which exhibit a dysregulated phenotype possibly due to oxidative stress. Mature macrophages and foam cells are thought to promote plaque rupture by eroding the fibromuscular cap. This is likely achieved through release of matrix-degrading proteases and also via FasL-mediated cytotoxic effects on adjacent vascular smooth muscle cells. Statins modulate both primary vascular release of MCP-1 and monocyte chemotaxis. In situ monocyte apoptosis might also contribute to their downstream effects on plaque stability.
Mentions: Monocyte turnover in solid tissue is determined by the balance between recruitment and clearance. Overproduction of monocyte chemoattractant protein (MCP-1) by native vascular cells and macrophages is a major mechanism promoting macrophage accumulation in atherosclerotic [32,33] and neointimal [34,35] lesions. Statin treatment was recently shown to down-regulate MCP-1 production in vitro and in vivo [36]; and to suppress the release of various other atherothrombotic mediators by plaque macrophages [15,36-40]. However, in most cases, the potential contribution of cell death to these findings was not concurrently investigated. Here we show that HMG-CoA reductase inhibition suppressed the release of IL-1Ra from LPS-stimulated monocytes; but that this suppression was largely accounted for by apoptotic cell death. Unlike IL-1β, the release of which occurs via stimulation of the P2X7 receptor at the level of the cell surface [41] and is thus refractory to apoptosis, secretion of IL-1Ra follows the classical pathway, which is effectively shut down during apoptosis [42]. While suppression of endothelial MCP-1 synthesis might genuinely contribute to the benefits of statin therapy, we suggest that induction of monocyte apoptosis may underlie many downstream statin actions, including the reduction in plaque macrophage counts and inhibition of in situ MMP and TF production [37-40] (figure 4). It is noteworthy that, since osteoclasts are also developmentally derived from peripheral blood monocytes, this hypothesis fits well with the recently proposed role of statins as modulators of bone formation [43].

Bottom Line: Immunomodulatory actions, independent of their lipid-lowering effect, have also been ascribed to these compounds.Concurrent treatment with mevalonolactone prevented the induction of apoptosis and suppressed both IL-1beta and IL-1Ra release in response to LPS, suggesting a rate-limiting role for HMG-CoA reductase in monocyte differentiation.Our findings indicate that statins arrest the functional differentiation of monocytes into macrophages and steer these cells into apoptosis, suggesting a novel mechanism for the vasculoprotective properties of HMG-CoA reductase inhibitors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, University of Cambridge, Cambridge, UK. joannis@scientist.com

ABSTRACT

Background: Statins effectively lower blood cholesterol and the risk of cardiovascular death. Immunomodulatory actions, independent of their lipid-lowering effect, have also been ascribed to these compounds. Since macrophages participate in several vascular pathologies, we examined the effect of statin treatment on the survival and differentiation of primary human monocytes.

Methods: Peripheral blood mononuclear cells (PBMCs) from healthy individuals were cultured in the presence or absence of mevastatin. Apoptosis was monitored by annexin V / PI staining and flow cytometry. In parallel experiments, cultures were stimulated with LPS in the presence or absence of mevastatin and the release of IL-1beta and IL-1Ra was measured by ELISA.

Results: Among PBMCs, mevastatin-treated monocytes were particularly susceptible to apoptosis, which occurred at doses >1 microM and was already maximal at 5 microM. However, even at the highest mevastatin dose used (10 microM), apoptosis occurred only after 24 h of culture, possibly reflecting a requirement for cell commitment to differentiation. After 72 h of treatment the vast majority (>50%) of monocytes were undergoing apoptosis. Stimulation with LPS revealed that mevastatin-treated monocytes retained the high IL-1beta output characteristic of undifferentiated cells; conversely, IL-1Ra release was inhibited. Concurrent treatment with mevalonolactone prevented the induction of apoptosis and suppressed both IL-1beta and IL-1Ra release in response to LPS, suggesting a rate-limiting role for HMG-CoA reductase in monocyte differentiation.

Conclusions: Our findings indicate that statins arrest the functional differentiation of monocytes into macrophages and steer these cells into apoptosis, suggesting a novel mechanism for the vasculoprotective properties of HMG-CoA reductase inhibitors.

Show MeSH
Related in: MedlinePlus